Nucleotide-binding oligomerization domain-like receptors (“NLRs”) include a family of intracellular receptors that detects pathogen-associated molecular patterns (“PAMPs”) and endogenous molecules (see, e.g., .P. -Y. Ting, et al., “The NLR gene family: a standard nomenclature,” Immunity, vol. 28, no. 3, pp. 285-287, 2008).
NLRPs represent a subfamily of NLRs that include a Pyrin domain and are constituted by proteins such as NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, and NLRP12. NLRPs are believed to be involved with the formation of multiprotein complexes termed inflammasomes (see, e.g., C. Chaput, et al., “NOD-like receptors in lung diseases,” Frontiers in Immunology, vol. 4, article 393, 2013). These complexes typically include one or two NLR proteins, the adapter molecule apoptosis associated speck-like containing a CARD domain (ASC) and pro-caspase-1 F (see, e.g., Bauernfeind and V. Hornung, “Of inflammasomes and pathogens—sensing of microbes by the inflammasome,” EMBO Molecular Medicine, vol. 5, no. 6, pp. 814-826, 2013).
One such inflammasome is formed by the NLRP3 scaffold, the ASC adaptor and caspase-1 (see, e.g., J. A. Hirota, et al., “The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter,” Journal of Allergy and Clinical Immunology, vol. 129, no. 4, pp. 1116.e6-1125.e6, 2012), and its expression is believed to be induced by inflammatory cytokines and TLR agonists in myeloid cells and human bronchial epithelial cells (Id.). The NLRP3 inflammasome is believed to mediate the caspase-1-dependent conversion of pro-IL-1β and pro-IL-18 to IL -1β and IL-18. Further, IL-1β and IL-18 have been shown to play an important role in the treatment of various types of cancer (see, e.g., EMBO Mol Med. 2012 4:1276 and PLoS One 2011 6:e24241). IL-18 has been shown to override resistance to checkpoint inhibitors in colon cancer tumor models (Clin. Cancer Res. 2016 Jan. 11. pii: clincanres.1655.2015).
Toll-Like Receptors (“TLRs”) are a family of receptors, which have been shown to recognize a structural diversity of PAMPs like glycans, lipids, proteins, lipoproteins, and nucleic acids and are and are believed to play a key role in the inflammatory and innate immune response. TLRs are expressed in various cellular compartments. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11 are predominantly expressed on the cell surface, while TLR3, TLR7, TLR8, TLR9, and TLR13 are expressed in intracellular vesicles such as the endoplasmic reticulum, endosomes, lysosomes, and endolysosomes and mainly recognize nucleic acid. TLRs are expressed in a broad variety of cells such as dendritic cells, macrophages, neutrophils, monocytes, T and B cells, epithelial cells, endothelial cells, fibroblasts, and even neural cells. It has also been reported that plasmacytoid dendritic cells and mast cells express TLR7 and TLR8, respectively. See, e.g., Javier Oviedo-Boyso, et al., “Collaborative Action of Toll-Like and Nod-Like Receptors as Modulators of the Inflammatory Response to Pathogenic Bacteria,” Mediators of Inflammation, vol. 2014, Article ID 432785, 16 pages, 2014. doi:10.1155/2014/432785